Historic Procedure Also Marks First In Vivo Gene Therapy in Adult Brain

NEW YORK(Aug 20, 2003)

Surgeons at NewYork-Presbyterian/Weill Cornell performed the world's first gene therapy for Parkinson's disease on a 55-year-old New York man on Monday, August 18. The historic surgery, which also marked the first-ever in vivo gene therapy in the brain for an adult neurological disease, was part of a Phase I clinical trial approved by the Food and Drug Administration in October 2002.

The five-hour procedure was performed by Dr. Michael G. Kaplitt, Director of Stereotactic and Functional Neurosurgery at NewYork-Presbyterian Hospital and Assistant Professor of Neurological Surgery at Weill Cornell Medical College. The patient is recovering normally and is expected to return home today, just two days after the surgery was performed.

"Monday's surgery represents the realization of nearly 15 years of research in this area," said Dr. Kaplitt. "The goal of our gene therapy approach is to 're-set' a specific group of cells that have become overactive in an affected part of the brain, causing the impaired movements associated with Parkinson's disease. We hope that this trial, which is the first of its kind, will prove to be a safe treatment to allow gene therapy to move forward for Parkinson's disease and other brain disorders."

Dr. Antonio M. Gotto, Jr., Dean of Weill Cornell Medical College, said: "This research represents a new approach to treating one of the most devastating diseases known to man."

Dr. Herbert Pardes, President and CEO of NewYork-Presbyterian Hospital, said, "This major breakthrough can only be realized in an academic medical center, such as ours, where a unique synergy between bench and bedside, between research and patient care, can meet and flourish."

In the procedure, Dr. Kaplitt pinpoints the optimal location in the patient's brain using information from an advanced 3T MRI image, which is subsequently merged with a CT scan, using the latest computer imaging technology. Then, the final target is confirmed using fine electrical probes that identify the signature pattern of electrical activity of individual cells within the brain. During this process, the patient is awake and not medicated because medication and anesthesia can confuse the electrical information obtained. With the target obtained, the gene therapy agent (adeno-associated virus or AAV) is slowly delivered through a very fine catheter. After a 90-minute infusion, the catheter is removed, the skin closed, and the patient sent to the recovery room.

AAV is the means by which the GAD (glutamic acid decarboxylase) gene enters the appropriate brain cells and begins production of a protein that produces GABA—a molecule that is released by nerve cells to inhibit, or dampen, activity. "Our intent, ultimately, is to normalize the chemical signaling of key affected brain areas in order to reduce the devastating effects of Parkinson's," says Dr. Kaplitt.

In 1994, Dr. Kaplitt was the lead author of a paper published in Nature Genetics, along with senior author Dr. Matthew During, Professor of Molecular Medicine at the University of Auckland, which demonstrated, for the first time, that AAV could be a safe and effective vehicle for gene therapy in the brain. Last October, Dr. During was the lead author and Dr. Kaplitt the co-author of a paper in Science demonstrating the feasibility of the gene therapy approach used in today's operation. Since 1994, AAV has been used safely in several clinical gene therapy trials, and the virus has never been associated with any human disease.

Dr. During, who is a co-investigator of the current clinical trial, along with Dr. Kaplitt, observes: "After years of focused effort, our technology and approach have reached a state of maturation where the risks are acceptable and the potential benefits sufficient to bring gene therapy to the clinic for neurological disorders. Nevertheless, we realize that this is but a first step in the long road of research and refinement toward developing effective gene therapies for the brain."

Although medical therapy is usually effective for most symptoms of Parkinson's early in the disease, over time many patients become resistant to treatment or develop disabling side effects. Deep Brain Stimulation (DBS), which is a surgical therapy in which electrodes are implanted deep into the brain, can provide some relief to many of these patients. But Dr. Kaplitt, who regularly performs DBS, notes that while it is the best treatment currently available, gene therapy would eliminate the need for brain electrodes and batteries characteristic of DBS, and could eventually be an improvement over DBS if this study proves that the therapy is safe.

As part of the Phase I trial, patients are being recruited and followed by Drs. David Eidelberg and Andrew Feigin at the North Shore University Hospital Movement Disorders Center. The initial trial will be limited to 12 patients with severe Parkinson's disease, of at least five-year's duration, for whom current therapies are no longer satisfactory.

"Our primary objective has been to stress patient safety above all else, and the NIH (National Institutes of Health) and FDA have helped us design a clinical intervention which has exciting efficacy potential but attempts to minimize as far as possible any risks of adverse events to patients in the study. It is our hope that with this approach, our trial will begin a process that hopefully will lead to safe and effective gene therapy in the brain," say Drs. Kaplitt and During.

Since 1990, gene therapy has been used in clinical trials for a variety of conditions, including cystic fibrosis, cardiovascular disease, infectious diseases such as AIDS, and cancer. In the neurological arena, there has previously been one study of direct, or in vivo, gene therapy for a rare pediatric neurogenetic disorder called Canavan's disease to try to protect cells that are dying. And there has been one study for Alzheimer's disease using transplanted cells which have been genetically modified in a dish to make a growth factor that might protect certain cells (so-called ex-vivo gene therapy). But the current study marks the first time that a gene has ever been put directly into an adult patient's own brain cells in an attempt to treat a neurological disease. Moreover, it is the first time that a gene has been put into the human brain not to protect cells, but with the intent of changing the very function of existing brain cells in order to alter overall brain function—representing a radically different concept than the two previous gene therapy brain trials.